A genetic vulnerability that is present in nearly 10% of all breast cancer tumours has been discovered, scientists have announced.
Research, published in yesterday’s (9 September 2020) edition of Nature, found that cells originating from a specific subset of human breast cancer tumours could be killed with a chemical that inhibits PLK4, an enzyme that is important for the centrosome.
Centrosomes perform important functions during cell division, regulating the process in which copies of each chromosome are accurately segregated between two identical daughter cells.
Cells normally have safety mechanisms that protect them from losing their centrosomes, but the research team from the University of Oxford working with the Johns Hopkins University School of Medicine in Baltimore, USA, found that these breast cancer cells could not survive without centrosomes.
Looking to establish if the cancer cells they were studying had a genetic change that made them especially reliant on their centrosomes, the team, led by Professor Ross Chapman, examined 17q23 amplification, a genetic abnormality that has a high incidence in breast cancer.
Experiments revealed that the TRIM37 gene was more active in cells that had 17q23 amplification and the researchers went on to show overactive TRIM37 resulted in faulty centrosomes, which in turn led to mistakes during cell division.
Prof Chapman, of the MRC Weatherall Institute of Molecular Medicine, said: “We think that what is happening is that if cells acquire too many copies of TRIM37, the normally very carefully orchestrated process of cell division goes haywire, which in turn leads to our genomes becoming unstable.
“This kind of genomic instability, where cells acquire all sorts of alterations to their genomes as they divide, is one of the hallmarks of cancer development.”
This means cells with the 17q23 amplification are more likely to become cancerous.
The research team also found that the same defect leaves the cells entirely reliant on their centrosomes for cell division, which is key to tumour development and used a drug that targets PLK4 and causes cells to lose their centrosomes, to kill cancer cells with 17q23 amplification.
Prof Chapman added: “It is slightly ironic that the same thing that makes the cells more likely to become cancerous also makes them uniquely vulnerable to losing their centrosomes, but is useful to us as scientists, because it means that we may be able to selectively target this kind of cancer cell in patients without affecting their healthy cells.”
The chemical PLK4 inhibitor used to deplete centrosomes in cancer cells is not suitable for use in patients, but the researchers hope their findings could lead to new PLK4-targeting drugs that have the same effect.
Nature 9 September 2020
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